Uptake of the neuron‐blocking agent meta‐iodobenzylguanidine and serotonin by human platelets and neuro‐adrenergic tumour cells

Abstract

The adrenomedulla-imaging agent meta-iodobenzylguanidine (MIBG) is concentrated by various tumours of neuroectodermal origin. Radio-iodinated [131I]MIBG is therefore increasingly used for diagnosis and therapy of these disorders. To study the cause of thrombocytopenia associated with [131I]MIBG therapy, we investigated the uptake of MIBG in human platelets in comparison with that of serotonin. Specific imipramine-sensitive uptake of [131I]MIBG was much slower than of [3H]serotonin, but after prolonged incubation high and serotonin-equivalent uptake levels were observed. Accumulation of MIBG saturated at 10- to 100-fold higher concentration than serotonin, and the affinity for uptake and intracellular storage in platelets was much higher for serotonin than for MIBG. Conversely, serotonin was not detectably concentrated by neuroadrenergic Uptake-I in SK-N-SH neuroblastoma and PC12 pheochromocytoma cells. Fluvoxamine inhibited the uptake of norepinephrine and MIBG in PC12 cells, similarly to that of serotonin in platelets. However, the drug was 100-fold more effective in inhibiting platelet transport of MIBG than of serotonin. The results indicate that MIBG uptake in platelets is not mediated by a neuro-adrenergic Uptake-I, but probably proceeds via the serotonin transport system. MIBG concentration by platelets was at least as efficient as in neuro-adrenergic tumour cells and has therefore (radio)biological potential for injuring these cells or precursor megakaryocytes. Platelet uptake of MIBG could be selectively blocked by fluvoxamine in concentrations which minimally affected its accumulation in neuro-adrenergic target cells.

Radioiodinated metaiodobenzylguanidine: a review of its biodistribution and pharmacokinetics, drug interactions, cytotoxicity and dosimetry

“…Uptake and storage of MIBG in thrombocytes are being investigated, since in general thrombocytes are thought to be a model for presynaptic adrenergic neurons (and hence for tumours derived from the adrenergic nerve system), being able to specifically take up NE and 5HT and showing amine storage granules [39]. However, Rutgers et al recently demonstrated that 5HT was not taken up specifically by PC-12 or SK-N-SH cells, which is an essential discriminator between these cells and thrombocytes [40]. These authors are interested in MIBG uptake and storage mechanisms of thrombocytes since thrombocytopenia is a frequent toxic side-effect of radionuclide therapy with [~3~I]MIBG.…”

“…These authors are interested in MIBG uptake and storage mechanisms of thrombocytes since thrombocytopenia is a frequent toxic side-effect of radionuclide therapy with [~3~I]MIBG. Specific uptake of 10 nM 5HT in human thrombocytes is rapid and levels off within 1 h, in contrast to the slower specific uptake of 10 nM MIBG, which gives a plateau after 3 h at a similar level as 5HT [40]. Since 27 gM imipramine has no effect on pre-existing drug levels of both 5HT and MIBG in thrombocytes, it was concluded that retention of either drug is mainly based on granular sequestration [40].…”

“…Rutgers et al provided evidence, through experiments with fluvoxamine (a selective inhibitor of 5HT re-uptake), for uptake by the 5HT transporter [40]. However, Glowniak et al, who studied cells transfected with the human NE transporter, the rat 5HT transporter or the bovine dopamine transporter, reported that specific uptake of 20 nM MIBG is exclusively by the human NE transporter [41].…”

Targeting of meta-iodobenzylguanidine to SK-N-SH human neuroblastoma xenografts: Tissue distribution, metabolism and therapeutic efficacy

“…Important questions with regard to optimizing the radiation exposure of the tumor relative to that of the bone marrow, the dose-limiting tissue, have therefore yet to be answered. For instance, laboratory studies are required to understand and possibly control the [ 131 I]MIBG-induced thrombocytopenia which occurs (Rutgers et al, 1993;Matthay et al, 1998).…”

Bioavailability and toxicity after oral administration of m-iodobenzylguanidine (MIBG)

“…The accumulation of MIBG in normal and neoplastic tissues of neuroadrenergic origin is based on its affinity for the specific uptake-1 mechanism of catecholamines (Jaques et al, 1987;Smets et al, 1991). Because of crossaffinity for the serotonin transporter (Rutgers et al, 1993), [ 131 l]MIBG is also applied for diagnosis and treatment of carcinoid tumours (Hoefnagel et al, 1987b;Taal et al, 1996a).…”